Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors

Eur J Pharmacol. 2013 Jan 5;698(1-3):228-34. doi: 10.1016/j.ejphar.2012.11.023. Epub 2012 Nov 23.


The effect of the (R,S)-ketamine metabolites (R,S)-norketamine, (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine on the activity of α7 and α3β4 neuronal nicotinic acetylcholine receptors was investigated using patch-clamp techniques. The data indicated that (R,S)-dehydronorketamine inhibited acetylcholine-evoked currents in α7-nicotinic acetylcholine receptor, IC(50) = 55 ± 6 nM, and that (2S,6S)-hydroxynorketamine, (2R,6R)-hydroxynorketamine and (R,S)-norketamine also inhibited α7-nicotinic acetylcholine receptor function at concentrations ≤ 1 μM, while (R,S)-ketamine was inactive at these concentrations. The inhibitory effect of (R,S)-dehydronorketamine was voltage-independent and the compound did not competitively displace selective α7-nicotinic acetylcholine receptor ligands [(125)I]-α-bungarotoxin and [(3)H]-epibatidine indicating that (R,S)-dehydronorketamine is a negative allosteric modulator of the α7-nicotinic acetylcholine receptor. (R,S)-Ketamine and (R,S)-norketamine inhibited (S)-nicotine-induced whole-cell currents in cells expressing α3β4-nicotinic acetylcholine receptor, IC(50) 3.1 and 9.1 μM, respectively, while (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine were weak inhibitors, IC(50) >100 μM. The binding affinities of (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine at the NMDA receptor were also determined using rat brain membranes and the selective NMDA receptor antagonist [(3)H]-MK-801. The calculated K(i) values were 38.95 μM for (S)-dehydronorketamine, 21.19 μM for (2S,6S)-hydroxynorketamine and>100 μM for (2R,6R)-hydroxynorketamine. The results suggest that the inhibitory activity of ketamine metabolites at the α7-nicotinic acetylcholine receptor may contribute to the clinical effect of the drug.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / antagonists & inhibitors*
  • Acetylcholine / pharmacology*
  • Anesthetics / chemistry
  • Anesthetics / metabolism
  • Anesthetics / pharmacology
  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Electrophysiological Phenomena / drug effects*
  • Ketamine / chemistry
  • Ketamine / metabolism*
  • Ketamine / pharmacology*
  • Nicotinic Agonists / pharmacology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Nicotinic / metabolism*
  • alpha7 Nicotinic Acetylcholine Receptor


  • Anesthetics
  • Chrna7 protein, rat
  • Nicotinic Agonists
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • Ketamine
  • Acetylcholine